Obesity is a serious health crisis with significant associated morbidity and mortality. It is estimated that about 64% of Americans are overweight or obese (roughly about 97 million adults) with a general belief that the proportion of overweight or obese people continues to rise. The prevalence of obesity worldwide is also believed to be increasing; the World Health Organization projects 700 million adults will be clinically obese (BMI≧30, body mass index; kg/m2) by 2015. Co-morbidities include type 2 diabetes, hypertension, dyslipidemia, heart disease, stroke, arthritis, gallstones, liver problems, sleep apnea and even some cancers (e.g., endometrial, breast, prostate, and colon cancers). Higher body weights are also associated with increases in all-cause mortality.
Numerous treatments for obesity have been developed over time, although no treatment has ever gained general acceptance. One of these treatments, fenfluramine-phentermine (commonly known as “fen-phen”), which targets human serotonin receptor 2C (HTR2C or the 5-HT2C receptor) protein, was very effective in achieving weight loss, however, it was withdrawn due to side effects such as pulmonary hypertension and heart valve damage. Eventually, it was determined that the side effects of fen-phen were due to their agonist activity at several serotonin receptors.
The 5-HT2C receptor belongs to the family of seven transmembrane domain receptors (7TMRs) that signal to the internal cellular environment via heterotrimeric guanine nucleotide-binding proteins (G proteins) in response to stimulation by hormones, neurotransmitters and pharmacological ligands. The 5-HT2C receptor is found primarily in the central nervous system, and particularly in the epithelial cells of the choroid plexus. The receptor is implicated in a range of other diseases, ranging from obesity-linked conditions such as Prader-Willi Syndrome (PWS) and hyperphagia to psychological disorders to sleep disorders to addiction.
Existing pharmaceutical HTR2C agonists, such as fen-phen and locaserin, function through directly targeting the HTR2C protein. Such HTR2C agonists would not be effective in treating diseases like Prader-Willi Syndrome (PWS), in which the HTR2C protein is dramatically reduced or even absent.